Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(6), P. 101080 - 101080

Published: June 1, 2023

CAR T cell persistence remains a significant roadblock to effective clinical translation of cells for solid and brain tumors. Jung et al.1Jung I.Y. Noguera-Ortega E. Bartoszek R. Collins S.M. Williams Davis M. Jadlowsky J.K. Plesa G. Siegel D.L. Chew A. al.Tissue-resident memory with stem-like characteristics display enhanced efficacy against liquid tumors.Cell Rep. Med. 2023; 4: 101053https://doi.org/10.1016/j.xcrm.2023.101053Abstract Full Text PDF Google Scholar demonstrate enrichment resident phenotypes through simple changes the manufacturing process. Chimeric antigen receptor (CAR) are gaining momentum as safe treatments tumors; however, improving anti-tumor challenge field. The mechanism by which kill tumor is straightforward. Synthetic molecules designed recognize specific antigens redirect cytotoxic machinery antigen-expressing cells, kill. subsequently activate expand, promoting further killing. However, it well established that progressively lose effector function after repeat exposure resulting in incomplete clearance recurrence. This gradual functional loss inability expand persist collectively defined exhaustion. To overcome exhaustion, field exploring strategies manipulating programs so sustained long term. Targeting epigenetic has emerged potential way accomplish this. Indeed, several groups have explored methods re-programming long-term targeting programs. In human deletion TET2,2Jain N. Zhao Z. Feucht J. Koche Iyer Dobrin Mansilla-Soto Yang Zhan Y. Lopez al.TET2 guards unchecked BATF3-induced expansion.Nature. 615: 315-322Crossref PubMed Scopus (0) DNMT3A,3Prinzing B. Zebley C.C. Petersen C.T. Fan Anido A.A. Yi Nguyen P. Houke H. Bell Haydar D. al.Deleting DNMT3A prevents exhaustion enhances antitumor activity.Sci. Transl. 2021; 13eabh0272Crossref (56) or SUV39H14Jain Gozlan Brocks Raveh-Sadka T. Wells Shi al.Abstract 5583: SUV39H1 disruption CD28-costimulated cells.Cancer Res. 2022; 82: 5583Crossref significantly survival, proliferation, function. these examples, requires regulators via gene editing cells. While knockout approaches now field, clinic still highly tedious, time consuming, expensive due regulatory requirements. Thus, alternative simplistic needed. One strategy been tweaking protocol addition chemical reagents. Multiple studies demonstrated dasatinib during not only primes adopt memory-like phenotype, reprograms transcriptional profiles, vitro vivo,5Weber, W.; Parker, K. R.; Sotillo, E.; Lynn, C.; Anbunathan, H.; Lattin, J.; Good, Z.; Belk, A.; Daniel, B.; Klysz, D., al, Transient rest restores functionality exhausted CAR-T remodeling. Science (New York, N.Y.) 2021, 372.Google but also overcomes fratricide.6Watanabe Mo F. Zheng Ma Bray V.C. van Leeuwen D.G. Sritabal-Ramirez Hu Wang S. Mehta al.Feasibility preclinical CD7-unedited CD7 malignancies.Mol. Ther. 31: 24-34Abstract Addition decitabine, an DNA methyltransferase (DNMT) inhibitor, shows promise priming improved function.7Wang Li Chen L. Bian X. Q. Xu Liu al.Low-dose decitabine endows persistent antitumour reprogramming.Nat. Commun. 6: 409Crossref (75) current study published Cell Reports Medicine, Jung. developed method products can be enriched tissue-resident (TRM) encourage accumulation tissue. many blood cancers benefit from actively circulate bloodstream bone marrow, treatment tumors cellular programming encourages cytolytic at location resist recirculation. this, al. optimized production activated generated presence exogenous transforming growth factor β (TGF-β) (Figure 1). TGF-β numerous functions on including maintenance naive/stem-like populations implication preserved tissue retention,8Mackay L.K. Rahimpour J.Z. Stock A.T. Hafon M.L. Vega-Ramos Lauzurica Mueller S.N. Stefanovic al.The developmental pathway CD103(+)CD8+ skin.Nat. Immunol. 2013; 14: 1294-1301Crossref (824) reduction CD8+ function.9Oh S.A. M.O. TGF-β: guardian function.J. 191 (1950): 3973-3979Crossref (202) Mesothelin (M5)-targeted interleukin-2 (IL-2) (CAR-TRM cells) were analyzed surface markers (via flow cytometry), profiles bulk single-cell RNA sequencing), chromatin accessibility assay transposase-accessible using sequencing [ATAC-seq]) confirm CAR-TRM phenotypes. indeed showed increased expression regulation TRM phenotype compared IL-2 alone. Importantly, analysis revealed downregulation KLF2 loci dictates commitment recirculation, suggesting residence discourage circulation. associated stemness, self-renewal, early traditional markers. superior cytokine upon stimulation control reduced genes responsible terminal differentiation dysfunction. suggests exhaustive decoupled terminally exhausted. produced vivo models both (pancreatic prostate) (B leukemia) cancers. Specifically, administration resulted higher overall number tissues two weeks following treatment. Improved was observed days administration. animals received successfully cleared rechallenges, residency Due known inhibitory attempted enrich overexpressing RUNX3 activation CD25, they ultimately failed induce exciting promising results, there some questions remain addressed. For example, this performed B leukemia settings. It would interesting see whether results consistent more challenging hematological malignancies such acute myeloid leukemia. addition, multiple try block signaling because its immunosuppressive effect cells.10de Folmont Bourhis J.-H. Chouaib Terry Multifaceted Role Transforming Growth Factor Therapy.Immuno. 1: 160-173Crossref know suppressive effects TME where secreted infiltrating immune immune-competent animal warranted. summary, demonstrates small tweaks generate ability penetrate additional pre-clinical testing warranted, shown easily manipulate potentially easy clinic. G.K. one-time consultant Kineticos (2022).

Language: Английский